Respiratory syncytial virus (RSV), a member of the paramyxoviridae family, is the leading cause of viral pneumonia and bronchitis in infants and young children worldwide, and is a major cause of fatal respiratory tract disease. Serious disease is most prevalent in infants 6 weeks to 6 months of age and in children with certain underlying illnesses (e.g., immunodeficiencies, congenital heart disease and bronchopulmonary dysplasia). Virtually all children are infected by two years of age. Most infections are symptomatic and are generally confined to mild upper respiratory tract disease. A decrease in severity of disease is associated with two or more prior infections and, in some studies, with high levels of serum antibody, suggesting that protective immunity to RSV disease will accumulate following repeated infections (Lamprecht, C. L. et al., J. Inf. Dis. 134:211-217 (1976); Henderson, F. W. et al., N. Eng. J. Med. 300:530-534 (1979); Glezen, W. P. et al., J. Ped. 98:706-715 (1981); Glezen, W. P. et al., Am. J. Dis. Child. 140:543-546 (1986); Kasel, J. A. et al., Vir. Immunol. 1:199-205 (1987/88); Hall, C. B. et al., J. Inf. Dis. 163:693-698 (1991)).
Two major subgroups of RSV have been identified, A and B, as well as antigenic variants within each subgroup (Anderson, L. J. et al., J. Inf. Dis. 151:626-633 (1985); Mufson, M. A. et al., J. Gen. Virol. 66:2111-2124 (1985)). Multiple variants of each subgroup have been found to co-circulate in epidemics which occur annually during late fall, winter, and spring months (Anderson, L. J. et al., J. Inf. Dis. 163:687-692 (1991)). There is evidence that children infected with one of the two major RSV subgroups may be protected against reinfection by the homologous subgroup (Mufson, M. A. et al., J. Clin. Microbiol. 26:1595-1597 (1987)). This, along with evidence that protective immunity will accumulate following repeated infections, suggests that it is feasible to develop an RSV vaccination regiment for infants and young children which would provide sufficient immunity to protect against disease and death.
A previous attempt to vaccinate young children against RSV employed a parenterally administered formalin-inactivated RSV vaccine. Unfortunately, administration of this vaccine in several field trials was shown to be associated with the development of a significantly exacerbated illness following subsequent natural infection with RSV (Kapikian, A. Z. et al., Am. J. Epidemiol. 89:405-421 (1968); Kim, H. W. et al., Am. J. Epidemiol. 89:422-434 (1969); Fulginiti, V. A. et al., Am. J. Epidemiol. 89:435-448 (1969); Chin, J. et al., Am. J. Epidemiol. 89:449-463 (1969)).
Following the lack of success with the formalin-inactivated RSV vaccine, emphasis was placed on the development of live attenuated vaccines. For example, cold adaptation, a process by which virus is adapted to grow at temperatures colder than those at which it normally optimally grows, has been used to develop temperature sensitive, attenuated RSV mutants for consideration as vaccines (Maassab, H. F. et al., Vaccine 3:355-369 (1985)). Unlike chemical mutagenesis in which the genetic lesions are usually single, this method generally results in the accumulation of multiple genetic lesions. These multiple lesions would help to confer phenotypic stability by reducing the probability that reversion of any one lesion will result in reversion to virulence. Stepwise cold adaptation, wherein the virus is passaged multiple times at progressively lower temperatures, has been used to successfully develop several influenza vaccine candidates currently in clinical trials (Maassab, H. F. et al., Viral Vaccines Wiley-Liss, Inc. (1990); Obrosova-Serova, N. P. et al., Vaccine 8:57-60 (1990); Edwards, K. M. et al., J. Inf. Dis. 163:740-745 (1991)). These mutants, which bear attenuating mutations in at least four different genes, appear to be attenuated, immunogenic, and phenotypically stable.
RSV was cold-adapted to 25-26.degree. C. in several laboratories in the mid-1960's, but was found to be under-attenuated in vaccine trials (Kim, H. W. et al., Pediatrics 48:745-755 (1971); Maassab, H. F. et al., Vaccine 3:355-369 (1985)). However, it is of note that administration of these live RSV vaccine candidates was never associated with disease enhancement following natural infection.
Live attenuated vaccines offer several advantages over inactivated vaccines. These include the possible use of a single dose and administration by the natural route of infection i.e., intranasally. In addition, live attenuated vaccines stimulate a wide range of immune responses, including local and serum antibody responses and cellular immunity. Furthermore, these vaccines are cost-effective and can be rapidly produced and updated in the event of antigenic changes.
It would thus be desirable to provide avirulent (attenuated), immunoprotective and genetically-stable live attenuated RSV strains. It would further be desirable to provide a vaccine comprising such attenuated strains. It would further be desirable to provide methods of making and using said RSV vaccine to protect against disease caused by infection with RSV.